The discovery of somatic mutations in epidermal growth receptor (EGFR) in patients who show dramatic response to reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has introduced the concept of personalized therapy in lung cancer treatment. However, resistance to the inhibitors emerges within one to two years. The secondary EGFR-T790M mutation, in the gate-keeper position of the tyrosine kinase domain, is present in more than 50% of lung cancers with acquired resistance to gefitinib or erlotinib. Since treatment options for these patients are currently limited, novel strategies to prevent or overcome acquired resistance to EGFR TKIs are sorely needed. We have demonstrated that -catenin is upregulated and activated in lung cancer cells harboring EGFR mutations including EGFR-T790M. As aberrant activation of -catenin signaling can lead to human cancers, we hypothesize that -catenin plays an essential role in lung tumorigenesis caused by EGFR mutants and inhibiting its activation alone or in combination with irreversible EGFR inhibitors may be an alternative strategy to overcome resistance to gefitinib or erlotinib. Therefore, our specific aims are to: (1) Investigate the mechanisms by which EGFR mutants lead to accumulation, nuclear translocation, and activation of -catenin; (2) Investigate whether activation of -catenin is required for EGFR- T790M-driven lung cancer formation/progression in vivo; and (3) Evaluate the effectiveness of -catenin inhibition as a novel therapeutic strategy to overcome resistance to erlotinib or gefitinib. We believe that the experiments proposed here will provide novel insights into the detailed mechanisms by which EGFR mutations cause tumorigenesis and innovative approaches to overcome resistance to gefitinib or erlotinib, significantly impacting care of patients with lung cancer in the near future.